Xin Wan, University of Utah
College of Health, and Department of Endocrinology, Metabolism, and Diabetes
We hypothesized that PP2A activation is required for lipid-induced, ceramide-mediated arterial dysfunction. Mice haploinsufficient for dihydroceramide desaturase (des1+/-) and their wild-type littermates (des1+/+) were infused (iv) for 6 h with lard-oil (LO) or vehicle (veh). Subgroups of LO and veh mice were treated (1.5 mg/kg IP) for 3 days prior to infusion with the PP2A inhibitor LB1 (Lixte Biotechnology, NY). LO increased ceramide accrual in arteries from des1+/+ but not des1+/mice. Palmitate (3 h x 500 uM) increased (p<0.05) PP2A activity, and impaired (p<0.05) insulin-stimulated p-eNOS(S) 1177 to eNOS in endothelial cells, and these responses were negated by LB1 (4 uM; n=5-8). Endothelium-dependent and -independent relaxation of femoral arteries (~ 150 um i.d.) was assessed using acetylcholine (ACh) and sodium nitroprusside (SNP), respectively (n=3 mice / group, 3 vessels / mouse). ACh-mediated (2×10-8, 3×10-8, and 6×10-8 M) relaxation (%) was less (p<0.05) in LO des1+/+ (30±2, 41±3, and 61±4, respectively) vs. veh des1+/+ mice (48±4, 67±6, and 73±6, respectively). Endothelial dysfunction observed in LO des1+/+ mice was less severe when ceramide accrual (i.e. LO des1+/mice) or PP2A activation (i.e., LB1 +LO des1+/+ mice) were prevented. SNP-evoked vasorelaxation was intact among groups. LO-induced ceramide accumulation induces endothelial dysfunction that is dependent upon PP2A activation. ADA1-12-BS-208, 2R15HL091493